Search

TNFα and related inflammatory factor antibody drugs have been orchestrated for the treatment of inflammatory bowel disease (IBD). However, antibody drugs elicited inevitable disadvantages and small molecule drugs are in an urgent need. Herein, we described the discovery, design, synthesis, and SAR studies from furanone glycoside compound Phoenicein (hit) isolated from Chimonanthus salicifolius to D228 (lead). Remarkably, D228 exhibited good inhibitory activity on B and T lymphocyte and excellent anti-IBD efficacy in vivo . Mechanistically, D228 alleviated the inflammation response by downregulating the MyD88/TRAF6/p38 signaling. Importantly, the relationship of D228 , Phoenicein , and their aglycone 7a was deduced: D228 could be considered as a prodrug and metabolized to intermediate Phoenicein . In turn, Phoenicein released their shared active aglycone 7a . Additionally, D228 demonstrated good and balanced profiles of safety and efficacy both in vitro and in vivo . These results suggested that D228 could be used as an ideal lead and potentially utilized for IBD chemotherapy.

SHP2 plays a critical role in modulating tumor growth and PD-1-related signaling pathway, thereby serving as an attractive antitumor target. To date, no antitumor drugs targeting SHP2 have been approved, and hence, the search of SHP2 inhibitors with new chemical scaffolds is urgently needed. Herein, we developed a novel SHP2 allosteric inhibitor SDUY038 with a furanyl amide scaffold, demonstrating potent binding affinity ( K D = 0.29 μM), enzymatic activity (IC 50 = 1.2 μM) and similar binding interactions to SHP099. At the cellular level, SDUY038 exhibited pan-antitumor activity (IC 50 = 7-24 μM) by suppressing pERK expression. Furthermore, SDUY038 significantly inhibited tumor growth in both xenograft and organoid models. Additionally, SDUY038 displayed acceptable bioavailability ( F = 14%) and half-life time ( t 1/2 = 3.95 h). Conclusively, this study introduces the furanyl amide scaffold as a novel class of SHP2 allosteric inhibitors, offering promising lead compounds for further development of new antitumor therapies targeting SHP2.

As a food contaminant that can be quickly absorbed through the gastrointestinal system, furan has been shown to disrupt the intestinal flora and barrier. Investigation of the intestinal toxicity mechanism of furan is of great significance to health. We previously identified the regulatory impact of salidroside (SAL) against furan-provoked intestinal damage, and the present work further explored whether the alleviating effect of SAL against furan-caused intestinal injury was based on the intestinal flora; three models, normal, pseudo-germ-free, and fecal microbiota transplantation (FMT), were established, and the changes in intestinal morphology, barrier, and inflammation were observed. Moreover, 16S rDNA sequencing observed the variation of the fecal flora associated with inflammation and short-chain fatty acids (SCFAs). Results obtained from the LC-MS/MS suggested that SAL increased furan-inhibited SCFA levels, activated the mRNA expressions of SCFA receptors ( GPR41 , GPR43 , and GPR109A ), and inhibited the furan-activated TLR4/MyD88/NF-κB signaling. Analysis of protein-protein interaction further confirmed the aforementioned effects of SAL, which inhibited furan-induced barrier damage and intestinal inflammation.

Herein, we describe the design and synthesis of γ-secretase modulator (GSM) clinical candidate PF-06648671 ( 22 ) for the treatment of Alzheimer's disease. A key component of the design involved a 2,5- cis -tetrahydrofuran (THF) linker to impart conformational rigidity and lock the compound into a putative bioactive conformation. This effort was guided using a pharmacophore model since crystallographic information was not available for the membrane-bound γ-secretase protein complex at the time of this work. PF-06648671 achieved excellent alignment of whole cell in vitro potency (Aβ42 IC 50 = 9.8 nM) and absorption, distribution, metabolism, and excretion (ADME) parameters. This resulted in favorable in vivo pharmacokinetic (PK) profile in preclinical species, and PF-06648671 achieved a human PK profile suitable for once-a-day dosing. Furthermore, PF-06648671 was found to have favorable brain availability in rodent, which translated into excellent central exposure in human and robust reduction of amyloid β (Aβ) 42 in cerebrospinal fluid (CSF).

Aggregative α-synuclein and incurring oxidative stress are pivotal cascading events, leading to dopaminergic (DAergic) neuronal loss and contributing to clinical manifestations of Parkinson's disease (PD). Our previous study demonstrated that 2-butoxytetrahydrofuran (2-BTHF), isolated from Holothuria scabra ( H. scabra ), could inhibit amyloid-β aggregation and its ensuing toxicity, which leads to Alzheimer's disease. In the present study, we found that 2-BTHF also attenuated the aggregative and oxidative activities of α-synuclein and lessened its toxicity in a transgenic Caenorhabditis elegans ( C. elegans ) PD model. Such worms treated with 100 μM of 2-BTHF showed substantial reductions in α-synuclein accumulation and DAergic neurodegeneration. Mechanistically, 2-BTHF, at this concentration, significantly decreased aggregation of monomeric α-synuclein and restored locomotion and dopamine-dependent behaviors. Molecular docking exhibited potential bindings of 2-BTHF to HSF-1 and DAF-16 transcription factors. Additionally, 2-BTHF significantly increased the mRNA transcripts of genes encoding proteins involved in proteostasis, including the molecular chaperones hsp-16.2 and hsp-16.49 , the ubiquitination/SUMOylation-related ubc-9 gene, and the autophagy-related genes atg-7 and lgg-1 . Transcriptomic profiling revealed an additional mechanism of 2-BTHF in α-synuclein-expressing worms, which showed upregulation of PPAR signaling cascades that mediated fatty acid metabolism. 2-BTHF significantly restored lipid deposition, upregulated the fat-7 gene, and enhanced gcs-1 -mediated glutathione synthesis in the C. elegans PD model. Taken together, this study demonstrated that 2-BTHF could abrogate aggregative and oxidative properties of α-synuclein and attenuate its toxicity, thus providing a possible therapeutic application for the treatment of α-synuclein-induced PD.

Inhibition of the NLRP3 inflammasome is a promising strategy for the development of new treatments for inflammatory diseases. MCC950 is a potent and selective small-molecule inhibitor of the NLRP3 pathway and has been validated in numerous species and disease models. Although the capacity of MCC950 to block NLRP3 signaling is well-established, it is still critical to identify the mechanism of action and molecular targets of MCC950 to inform and derisk drug development. Quantitative proteomics performed in disease-relevant systems provides a powerful method to study both direct and indirect pharmacological responses to small molecules to elucidate the mechanism of action and confirm target engagement. A comprehensive target deconvolution campaign requires the use of complementary chemical biology techniques. Here we applied two orthogonal chemical biology techniques: compressed Cellular Thermal Shift Assay (CETSA) and photoaffinity labeling chemoproteomics, performed under biologically relevant conditions with LPS-primed THP-1 cells, thereby deconvoluting, for the first time, the molecular targets of MCC950 using chemical biology techniques. In-cell chemoproteomics with inlysate CETSA confirmed the suspected mechanism as the disruption of inflammasome formation via NLRP3. Further cCETSA (c indicates compressed) in live cells mapped the stabilization of NLRP3 inflammasome pathway proteins, highlighting modulation of the targeted pathway. This is the first evidence of direct MCC950 engagement with endogenous NLRP3 in a human macrophage cellular system using discovery proteomics chemical biology techniques, providing critical information for inflammasome studies.

Alzheimer's disease (AD) is a neurodegenerative disorder caused by accumulation of amyloid-β oligomers (AβO) in the brain, neuroinflammation, oxidative stress, and cognitive decline. Grandisin, a tetrahydrofuran neolignan, exhibits relevant anti-inflammatory and antioxidant properties. Interestingly, grandisin-based compounds were shown to prevent AβO-induced neuronal death in vitro. However, no study has assessed the effect of these compounds on the AD animal model. This study focuses on a triazole grandisin analogue (TGA) synthesized using simplification and bioisosteric drug design, which resulted in improved potency and solubility compared with the parent compound. This study aimed to investigate the possible in vivo effects of TGA against AβO-induced AD. Male C57/Bl6 mice underwent stereotaxic intracerebroventricular AβO (90 μM) or vehicle injections. 24 h after surgery, animals received intraperitoneal treatment with TGA (1 mg/kg) or vehicle, administered on a 14 day schedule. One day after treatment completion, a novel object recognition task (NORT) was performed. Memantine (10 mg/kg) was administered as a positive control. NORT retention sessions were performed on days 8 and 16 after AβO injection. Immediately after retention sessions, animals were euthanized for cortex and hippocampus collection. Specimens were subjected to oxidative stress and cytokine analyses. TGA reduced the level of cortex/hippocampus lipoperoxidation and prevented cognitive impairment in AβO-injected mice. Additionally, TGA reduced tumor necrosis factor (TNF) and interferon-γ (IFN-γ) levels in the hippocampus. By contrast, memantine failed to prevent cortex/hippocampus lipid peroxidation, recognition memory decline, and AβO-induced increases in TNF and IFN-γ levels in the hippocampus. Thus, memantine was unable to avoid the AβO-induced persistent cognitive impairment. The results showed that TGA may prevent memory impairment by exerting antioxidant and anti-inflammatory effects in AβO-injected mice. Moreover, TGA exhibited a persistent neuroprotective effect compared to memantine, reflecting an innovative profile of this promising agent against neurodegenerative diseases, such as AD.

The inhibition of CXC chemokine receptor 2 (CXCR2), a key inflammatory mediator, is a potential strategy in the treatment of several pulmonary diseases and cancers. The complexity of endogenous chemokine interaction with the orthosteric binding site has led to the development of CXCR2 negative allosteric modulators (NAMs) targeting an intracellular pocket near the G protein binding site. Our understanding of NAM binding and mode of action has been limited by the availability of suitable tracer ligands for competition studies, allowing direct ligand binding measurements. Here, we report the rational design, synthesis, and pharmacological evaluation of a series of fluorescent NAMs, based on navarixin ( 2 ), which display high affinity and preferential binding for CXCR2 over CXCR1. We demonstrate their application in fluorescence imaging and NanoBRET binding assays, in whole cells or membranes, capable of kinetic and equilibrium analysis of NAM binding, providing a platform to screen for alternative chemophores targeting these receptors.

The NLRP3 inflammasome is a critical component of innate immunity involved in the pathophysiology of various inflammatory diseases. In this study, we designed and synthesized a series of NLRP3 inflammasome inhibitors based on MCC950. Specifically, we optimized the furan moiety, which is considered to be potentially associated with drug-induced liver injury. The representative inhibitor N14 , 4-(2-(dimethylamino)ethyl)- N -((1,2,3,5,6,7-hexahydro- s -indacen-4-yl)carbamoyl)benzenesulfonamide, not only maintains the NLRP3 inhibitory activity of MCC950 with IC 50 of 25 nM but also demonstrates improved tolerability in human hepatic cells line and mouse primary hepatocytes. In addition, N14 exhibits superior pharmacokinetic properties, with an oral bioavailability of 85.2%. In vivo studies demonstrate that N14 is more effective than MCC950 in multiple NLRP3-related animal model diseases, including nonalcoholic steatohepatitis, lethal septic shock, and colitis. Our research has provided a lead compound that directly targets the NLRP3 inflammasome and can be developed as a novel therapeutic candidate for NLRP3-driven diseases.

Quorum sensing inhibitors (QSIs) are a class of compounds that can reduce the pathogenicity of bacteria without affecting bacterial growth. In this study, we designed and synthesized four series of 4-fluorophenyl-5-methylene-2(5 H )-furanone derivatives and evaluated their QSI activities. Among them, compound 23e not only showed excellent inhibitory activity against various virulence factors but also significantly enhanced the inhibitory activity of antibiotics ciprofloxacin and clarithromycin against two strains of Pseudomonas aeruginosa in vitro . What is even more exciting is that it remarkably increased the antibacterial effect in vivo in combination with ciprofloxacin in the bacteremia model infected with P. aeruginosa PAO1. Moreover, 23e had little hemolytic activity to mouse erythrocytes. Further, the results of GFP reporter fluorescence strain inhibition and β-galactosidase activity inhibition experiments demonstrated that 23e simultaneously targeted the three quorum sensing systems in P. aeruginosa . As a result, compound 23e could be used as an effective QSI for further development against bacterial infections.

Chemotherapy of human immunodeficiency virus type-1 (HIV-1) has significantly developed over the last three decades. The emergence of drug-resistant variants is, however, still a severe problem. The RNase H activity of HIV-1 reverse transcriptase is an attractive target for a new class of antiviral drugs because there is no approved inhibitor. The nitro-furan-carbonyl and nitro-thiophene-carbonyl groups are potent scaffolds for the HIV-1 RNase H inhibitor. In this work, the binding structures of six inhibitory compounds were obtained by X-ray crystal analysis in a complex with a recombinant protein of HIV-1 RNase H domain. Every inhibitory compound was found to be bound to the catalytic site with the furan- or thiophene-ring coordinated to two divalent metal ions at the binding pocket. All the atoms in nitro, furan, carbonyl, and two metals were aligned in the nitro-furan derivatives. The straight line connecting nitro and carboxyl groups was parallel to the plane made by two metal ions and a furan O atom. The binding modes of the nitro-thiophene derivatives were slightly different from those of the nitro-furan ones. The nitro and carbonyl groups deviated from the plane made by two metals and a thiophene S atom. Molecular dynamics simulations suggested that the furan O or thiophene S atom and carbonyl O atom were firmly coordinated to the metal ions. The simulations made the planar nitro-furan moiety well aligned to the line connecting the two metal ions. In contrast, the nitro-thiophene derivatives were displaced from the initial positions after the simulations. The computational findings will be a sound basis for developing potent inhibitors for HIV-1 RNase H activity.

Cancer is one of the most serious health problems that usually require heavy medical treatment. It is important to ensure that no additional burden is placed on patients due to the modes of administration and/or poor quality of pharmaceuticals. In this regard, understanding, quantifying, and improving the photostability (resistance to UV light or sunlight) of drugs is among the important elements that can improve the patient's quality of life. In this work, the photochemical properties of a wide range of furanone analogues of combretastatin A-4 and their antiproliferative activity against A-431 epidermoid carcinoma cells were studied in a search for compounds with improved photostability and antiproliferative activity. It was found that the incorporation of an arylidene moiety led to a significant improvement in photostability, while the antiproliferative activity strongly depends on the nature of the aryl residue in the arylidene moiety. The high photostability of arylidenes was achieved due to the delocalization of the central double bond of the 1,3,5-hexatriene system, which limited the 6π-electrocyclization. The best results in terms of antiproliferative activity were obtained for thiophene arylidene (IC 50 = 0.6 μM) and 3,4-diarylfuran (IC 50 = 0.047 μM). The obtained results address the lack of data available now in scientific literature on the photodegradation of combretastatin A-4 analogues and should be taken into account in studies of the side effects of pharmaceuticals based on them.

Janus kinase 3 (JAK3) is a potential target for the treatment of hematological malignancies. Herein, we report the discovery of a series of new orally bioavailable irreversible JAK3 kinase inhibitors. The representative compound 12n potently inhibited JAK3 kinase activity with an IC 50 value of 1.2 nM and was more than 900-fold selective over JAK1, JAK2, and Tyk2. Cell-based assays revealed that 12n significantly suppressed phosphorylation of JAK3 and the downstream effectors STAT3/5 and also robustly restrained proliferation of BaF3 cells transfected with JAK3 M511I activating mutation and human leukemia U937 cells harboring JAK3 M511I with IC 50 values of 22.9 and 20.2 nM, respectively. More importantly, 12n showed reasonable pharmacokinetic (PK) properties, and oral administration of 12n at a dose of 50 mg/kg twice daily led to tumor regression in a U937 cell inoculated xenograft mouse model. Thus, 12n represents a promising lead compound for further optimization to discover new therapeutic agents for hematological malignancies.

Here, we report the design, synthesis, structure-activity relationship studies, antiviral activity, enzyme inhibition, and druggability evaluation of dihydrofuro[3,4- d ]pyrimidine derivatives as a potent class of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Compounds 14b (EC 50 = 5.79-28.3 nM) and 16c (EC 50 = 2.85-18.0 nM) exhibited superior potency against a panel of HIV-1-resistant strains. Especially, for the changeling mutations F227L/V106A and K103N/Y181C, both compounds exhibited remarkably improved activity compared to those of etravirine and rilpivirine. Moreover, 14b and 16c showed moderate RT enzyme inhibition (IC 50 = 0.14-0.15 μM), which demonstrated that they acted as HIV-1 NNRTIs. Furthermore, 14b and 16c exhibited favorable pharmacokinetic and safety properties, making them excellent leads for further development.

Succinate dehydrogenase (SDH) is known as an ideal target for the investigations of fungicides. To develop novel SDH inhibitors, 30 novel thiophene/furan-1,3,4-oxadiazole carboxamide derivatives were designed and synthesized. In the in vitro antifungal assay, a majority of the target compounds demonstrated fair to potent antifungal activity against seven tested phytopathogenic fungi. Compounds 4b , 4g , 4h , 4i , and 5j showed remarkable antifungal activity against Sclerotinia sclerotiorum , affording EC50 values ranging from 0.1∼1.1 mg/L. In particular, compound 4i displayed the most potent activity against S. sclerotiorum (EC 50 = 0.140 ± 0.034 mg/L), which was superior to that of boscalid (EC 50 = 0.645 ± 0.023 mg/L). A further morphological investigation revealed the abnormal mycelia and damaged cell structures of compound 4i - treated S. sclerotiorum by scanning electron microscopy. Furthermore, the in vivo antifungal assay against S. sclerotiorum revealed that compounds 4g and 4i were effective for suppressing rape Sclerotinia rot at a dosage of 200 mg/L. In the SDH inhibition assay, compounds 4g and 4i also presented significant inhibitory activity with IC 50 values of 1.01 ± 0.21 and 4.53 ± 0.19 μM, respectively, which were superior or equivalent to that of boscalid (3.51 ± 2.02 μM). Molecular docking and molecular dynamics simulation of compound 4g with SDH revealed that compound 4g could form strong interactions with the key residues of the SDH. These results indicated that this class of derivatives could be a promising scaffold for the discovery and development of novel SDH inhibitors.

The profound efficacy of pan-BET inhibitors is well documented, but these epigenetic agents have shown pharmacology-driven toxicity in oncology clinical trials. The opportunity to identify inhibitors with an improved safety profile by selective targeting of a subset of the eight bromodomains of the BET family has triggered extensive medicinal chemistry efforts. In this article, we disclose the identification of potent and selective drug-like pan-BD2 inhibitors such as pyrazole 23 (GSK809) and furan 24 (GSK743) that were derived from the pyrrole fragment 6 . We transpose the key learnings from a previous pyridone series (GSK620 2 as a representative example) to this novel class of inhibitors, which are characterized by significantly improved solubility relative to our previous research.

Long residence time enzyme inhibitors with a two-step binding mechanism are characterized by a high internal energy barrier for target association. This raises the question of whether optimizing residence time via further increasing this internal energy barrier would inevitably lead to insufficient target occupancy in vivo due to slow, time-dependent binding. We attempted to address this question during optimization of cyclooxygenase-2 (COX-2) inhibitors. Defining long residence time drugs with acceptable association and dissociation rate constants required for sufficient target occupancy and sustained efficacy, which we termed "balanced internal energetics", provides an important criterion for successful progression during lead optimization. Despite the advancement of several COX-2 inhibitors to marketed drugs, their detailed inhibition kinetics have been surprisingly limiting especially during the structure-activity relationship process mainly due to the lack of robust kinetic assays. Herein, we describe a reoptimized COX enzymatic assay and a novel MS-based assay enabling detailed mechanistic studies for identifying long residence time COX-2 inhibitors with balanced internal energetics. These efforts led to the discovery of promising leads possessing dissociation half-lives of ≤40 h, much greater than the values of 6 and 0.71 h for two marketed drugs, etoricoxib and celecoxib, respectively. Importantly, the inhibition rate constants remain comparable to those of the marketed drugs and above the lower limits set by the criteria of balanced internal energetics, predicting sufficient target occupancy required for efficacy. Taken together, this study demonstrates the feasibility of increasing the internal energy barrier as a viable approach for lead optimization toward discovering long residence time drug candidates.

Inhibition of inflammasome and pyroptotic pathways are promising strategies for clinical treatment of autoimmune and inflammatory disorders. MCC950, a potent inhibitor of the NLR-family inflammasome pyrin domain-containing 3 (NLRP3) protein, has shown encouraging results in animal models for a range of conditions; however, until now, no off-targets have been identified. Herein, we report the design, synthesis, and application of a novel photoaffinity alkyne-tagged probe for MCC950 ( IMP2070 ) which shows direct engagement with NLRP3 and inhibition of inflammasome activation in macrophages. Affinity-based chemical proteomics in live macrophages identified several potential off-targets, including carbonic anhydrase 2 (CA2) as a specific target of IMP2070 , and independent cellular thermal proteomic profiling revealed stabilization of CA2 by MCC950. MCC950 displayed noncompetitive inhibition of CA2 activity, confirming carbonic anhydrase as an off-target class for this compound. These data highlight potential biological mechanisms through which MCC950 and derivatives may exhibit off-target effects in preclinical or clinical studies.

N -Methyl-d-aspartate receptors (NMDARs) are glutamate-gated Na + and Ca 2+ -permeable ion channels involved in excitatory synaptic transmission and synaptic plasticity. NMDAR hypofunction has long been implicated in the pathophysiology including major depressive disorders (MDDs). Herein, we report a series of furan-2-carboxamide analogues as novel NMDAR-positive allosteric modulators (PAMs). Through structure-based virtual screen and electrophysiological tests, FS2921 was identified as a novel NMDAR PAM with potential antidepressant effects. Further structure-activity relationship studies led to the discovery of novel analogues with increased potentiation. Compound 32h caused a significant increase in NMDAR excitability in vitro and impressive activity in the forced swimming test. Moreover, compound 32h showed no significant inhibition of hERG or cell viability and possessed a favorable PK/PD profile. Our study presented a series of novel NMDAR PAMs and provided potential opportunities for discovering of new antidepressants.

The main objective of this study was to determine whether ( E )-3-furan-2-yl- N - p -tolyl-acrylamide (PAM-2) and its structural derivative DM489 produce anti-neuropathic pain activity using the streptozotocin (STZ)- and oxaliplatin-induced neuropathic pain animal models. To assess possible mechanisms of action, the pharmacological activity of these compounds was determined at α7 and α9α10 nicotinic acetylcholine receptors (nAChRs) and Ca V 2.2 channels expressed alone or coexpressed with G protein-coupled GABA B receptors. The animal results indicated that a single dose of 3 mg/kg PAM-2 or DM489 decreases STZ-induced neuropathic pain in mice, and chemotherapy-induced neuropathic pain is decreased by PAM-2 (3 mg/kg) and DM489 (10 mg/kg). The observed anti-neuropathic pain activity was inhibited by the α7-selective antagonist methyllycaconitine. The coadministration of oxaliplatin with an inactive dose (1 mg/kg) of PAM-2 decreased the development of neuropathic pain after 14, but not 7, days of cotreatment. The electrophysiological results indicated that PAM-2 potentiates human (h) and rat (r) α7 nAChRs with 2-7 times higher potency than that for hCa V 2.2 channel inhibition and an even greater difference compared to that for rα9α10 nAChR inhibition. These results support the notion that α7 nAChR potentiation is likely the predominant molecular mechanism underlying the observed anti-nociceptive pain activity of these compounds.

The estrogen related receptors (ERRs) are a subgroup of nuclear receptors that play a role in regulation of cellular metabolism. Prostate cancer (PCa) cells display altered metabolic signatures, such as the Warburg effect, and the ERRs have been implicated in driving this phenotype. Despite the lack of a known endogenous ligand, synthetic ligands that target the ERRs have been discovered. For example, the ERRα inverse agonist XCT790 modulates metabolic pathways in PCa cells, but it also functions as a mitochondrial uncoupler independent of targeting ERRα. Here, we describe a novel dual ERRα/γ inverse agonist, SLU-PP-1072, derived from the GSK4716 ERRγ agonist scaffold that is distinct from the XCT790 scaffold. SLU-PP-1072 alters PCa cell metabolism and gene expression, resulting in cell cycle dysregulation and increased apoptosis without acute mitochondrial uncoupling activity. Our data suggest that inhibition of ERRα/γ may be beneficial in treatment of PCa, and SLU-PP-1072 provides a unique chemical tool to evaluate the pharmacology of ERRα and ERRγ.

The design, synthesis, and X-ray structural analysis of hybrid HIV-1 protease inhibitors (PIs) containing bis-tetrahydrofuran (bis-THF) in a pseudo-C 2 -symmetric dipeptide isostere are described. A series of PIs were synthesized by incorporating bis-THF of darunavir on either side of the Phe-Phe isostere of lopinavir in combination with hydrophobic amino acids on the opposite P2/P2' position. Structure-activity relationship studies indicated that the bis-THF moiety can be attached at either the P2 or P2' position without significantly affecting potency. However, the group on the opposite P2/P2' position had a dramatic effect on potency depending on the size and shape of the side chain. Cocrystal structures of inhibitors with wild-type HIV-1 protease revealed that the bis-THF moiety retained similar interactions as observed in the darunavir-protease complex regardless of the position on the Phe-Phe isostere. Analyses of cocrystal structures and molecular dynamics simulations provide insights into optimizing HIV-1 PIs containing bis-THF in non-sulfonamide dipeptide isosteres.

A series of novel furan-2-yl-1 H -pyrazoles and their chemical precursors were synthesized and evaluated for their effectiveness at disrupting α-synuclein (α-syn) aggregation in vitro . The compounds were found to inhibit α-syn aggregation with efficacy comparable to the promising drug candidate anle138b. The results of this study indicate that compounds 8b , 8l , and 9f may qualify as secondary leads for the structure-activity relationship studies aimed to identify the suitable compounds for improving the modulatory activity targeted at α-syn self-assembly related to Parkinson's disease.

We describe here design, synthesis, and biological evaluation of a series of highly potent HIV-1 protease inhibitors containing stereochemically defined and unprecedented tricyclic furanofuran derivatives as P2 ligands in combination with a variety of sulfonamide derivatives as P2' ligands. These inhibitors were designed to enhance the ligand-backbone binding and van der Waals interactions in the protease active site. A number of inhibitors containing the new P2 ligand, an aminobenzothiazole as the P2' ligand and a difluorophenylmethyl as the P1 ligand, displayed very potent enzyme inhibitory potency and also showed excellent antiviral activity against a panel of highly multidrug-resistant HIV-1 variants. The tricyclic P2 ligand has been synthesized efficiently in an optically active form using enzymatic desymmetrization of meso-1,2-(dihydroxymethyl)cyclohex-4-ene as the key step. We determined high-resolution X-ray structures of inhibitor-bound HIV-1 protease. These structures revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insights into the binding properties of these new inhibitors.

Flazin is a β-carboline-derived alkaloid found in Japanese fermented foods. Here, the potential of flazin as an antioxidant food was studied with particular reference to its effect on the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) system in human hepatocytes (C3A). Flazin and flazin analogues including the decarboxylated derivative perlolyrine were chemically synthesized and compared with each other and with chlorogenic acid and curcumin. Among these compounds, flazin showed the lowest cytotoxicity (IC 50 < 500 μM) and the highest capacity to activate the Keap1-Nrf2 system. It provided the largest (>3-fold of the control) cytoprotection ability against a pro-oxidant, although its radical absorbance capacity was relatively low. Flazin increased the expressions of Nrf2-dependent phase II enzyme genes and their products (NQO1, GSTP, and GSH proteins). The strong cytoprotection ability of flazin associated with low log  P (0-3) is shared by sulforaphane and 3,5-dihydroxy-4-methoxybenzyl alcohol, suggesting the potential value of flazin and flazin-rich foods for the prevention of oxidation-related health disorders.

Bacterial leaf blight (BLB) caused by Xanthomonas oryzae pv oryzae ( Xoo ) is considered as the most destructive disease of rice. The use of bactericides is among the most widely used traditional methods to control this destructive disease. The excessive and repeated use of the same bactericides is also becoming the reason behind the development of bactericide resistance. The widely used method for finding the new antimicrobial agents often involves the bacterial virulence factors as a target without affecting bacterial growth. Type III secretion system (T3SS) is a protein appendage and is considered as having essential virulence factors in most Gram-negative bacteria. Due to the conserved construct, T3SS has been regarded as an important mark for the blooming of novel antimicrobial drugs. Toward the search of new T3SS inhibitors, an alternative series of 1,3-thiazole derivatives were designed and synthesized. Their structures were characterized and confirmed by 1 H NMR, 13 C NMR, MS, and elemental analysis. All the title compounds inhibited the promoter activity of hpa1 gene significantly. Eight of them showed better inhibition than our previous T3SS inhibitor TS006 ( o -coumaric acid, OCA). The treatment of Xoo with eight compounds significantly attenuated HR without affecting bacterial growth. The mRNA levels of some representative genes ( hrp / hrc genes) were reduced up to different extents. In vivo bioassay results showed that eight T3SS inhibitors could reduce bacterial leaf blight and bacterial leaf streak symptoms on rice, significantly.

The limited number of agrochemicals targeting plant bacterial diseases has driven us to develop highly efficient, low-cost, and versatile antibacterial alternatives. Herein, a novel type of simple furan-functionalized quinazolin-4-amines was systematically fabricated and screened for their antibacterial activity. Bioassay results revealed that compounds C 1 and E 4 could substantially block the growth of two frequently mentioned pathogens Xanthomonas oryzae pv oryzae and X. axonopodis pv citri in vitro, displaying appreciable EC 50 values of 7.13 and 10.3 mg/L, respectively. This effect was prominently improved by comparing those of mainly used agrochemicals. An in vivo experiment against bacterial blight further illustrated their viable applications as antimicrobial ingredients. Quantitative proteomics demonstrated that C 1 possessed a remarkable ability to manipulate the upregulation and downregulation of expressed proteins, which probably involved d-glucose and biotin metabolic pathways. This finding was substantially verified by parallel reaction monitoring analysis. Scanning electron microscopy images and fluorescence spectra also indicated that the designed compounds had versatile capacities for destroying the integrity of bacteria. Given these remarkable characteristics, furan-functionalized quinazoline hybrids can serve as a viable platform for developing innovative antibiotic alternatives against bacterial infections.

The search for compounds capable of targeting early pathological changes of Alzheimer̀s disease (AD), such as oxidative stress and neuroinflammation, is an important challenge. Gracilin A derivatives were recently synthesized, using a pharmacophore-directed retrosynthesis (PDR) strategy, and found to possess potent neuroprotective effects. In this work, the previously described derivatives 1 - 7 which demonstrated mitochondrial-mediated, antioxidant effects were chosen for further study. The ability of compounds to modulate the expression of antioxidant genes ( CAT , GPx , SODs , and Nrf2 ) was determined in SH-SY5Y cells, and the simplified derivatives 2 and 3 were found to be the most effective. The anti-neuroinflammatory properties of all derivatives were assessed in BV2 microglial cells activated with lipopolysaccharide (LPS). Several derivatives decreased the release of cytokines (Il-1β, IL-6, GM-CSF, and TNF-α) and other damaging molecules (ROS, NO) and also regulated the translocation of Nrf2 and NFκB, and reduced p38 activation. These protective effects were confirmed in a trans-well coculture with BV2 and SH-SY5Y cells and several derivatives increased SH-SY5Y survival. This present work demonstrates the neuroprotective properties of gracilin A derivatives, making them promising candidate drugs for AD. Particularly, derivatives 2 and 3 showed the greatest potential as lead compounds for further development.

ChEMBL biological activities prediction for 1-5-bromofur-2-il-2-bromo-2-nitroethene (G1) is a difficult task for cytokine immunotoxicity. The current study presents experimental results for G1 interaction with mouse Th1/Th2 and pro-inflammatory cytokines using a cytometry bead array (CBA). In the in vitro test of CBA, the results show no significant differences between the mean values of the Th1/Th2 cytokines for the samples treated with G1 with respect to the negative control, but there are moderate differences for cytokine values between different periods (24/48 h). The experiments show no significant differences between the mean values of the pro-inflammatory cytokines for the samples treated with G1, regarding the negative control, except for the values of tumor necrosis factor (TNF) and Interleukin (IL6) between the group treated with G1 and the negative control at 48 h. Differences occur for these cytokines in the periods (24/48 h). The study confirmed that the antimicrobial G1 did not alter the Th1/Th2 cytokines concentration in vitro in different periods, but it can alter TNF and IL6. G1 promotes free radicals production and activates damage processes in macrophages culture. In order to predict all ChEMBL activities for drugs in other experimental conditions, a ChEMBL data set was constructed using 25 biological activities, 1366 assays, 2 assay types, 4 assay organisms, 2 organisms, and 12 cytokine targets. Molecular descriptors calculated with Rcpi and 15 machine learning methods were used to find the best model able to predict if a drug could be active or not against a specific cytokine, in specific experimental conditions. The best model is based on 120 selected molecular descriptors and a deep neural network with area under the curve of the receiver operating characteristic of 0.904 and accuracy of 0.832. This model predicted 1384 G1 biological activities against cytokines in all ChEMBL data set experimental conditions.

We describe here the syntheses of optically pure (3a S ,4 S ,7a R )-hexahydro-4 H -furo[2,3- b ]pyran-4-ol and (3a R ,4 R ,7a S )-hexahydro-4 H -furo[2,3- b ]pyran-4-ol. These stereochemically defined heterocycles are important high-affinity P2 ligands for a variety of highly potent HIV-1 protease inhibitors. The key steps involve an efficient Paternò-Büchi [2 + 2] photocycloaddition, catalytic hydrogenation, acid-catalyzed cyclization to form the racemic ligand alcohol, and an enzymatic resolution with immobilized Amano Lipase PS-30. Optically active ligands (-)- 6 and (+)- 6 were obtained with high enantiomeric purity. Enantiomer (-)- 6 has been converted to potent HIV-1 protease inhibitor 3 .

A selective aziridinium ring-opening was used to etherify an α-aryl-β-amino alcohol with stereochemical retention. This transformation was achieved in a biphasic system to address phenoxide solubility and the formation of a sulfonate ester impurity. The protecting group strategy was directed by a stability study of the activated α-aryl-β-amino alcohol in this system. Process analytical techniques were used to establish reaction understanding, and mixing on large scale was modeled in silico. The process provided a selective and efficient method of preparing the nonsteroidal, inhaled selective glucocorticoid receptor modulator AZD7594.

Hsp70 is known to directly bind to Bax for suppression of apoptosis. However, mechanisms on how Bax is dissociated from its complex with Hsp70 during apoptosis remain largely unknown. In the current study, we developed the efficient fluorescence resonance energy transfer (FRET) system which consisted of Hsp70-YFP and fluorescent amino acid (ANAP)-incorporated Bax, which was generated by using genetic code expansion technology, and applied the FRET system to elucidate mechanisms on how apoptosis-inducing substances dissociate Bax from Hsp70. Time-dependent analysis of single live cell images showed that Bax activators binding to Bax trigger sites inhibited the Bax-Hsp70 interaction but a Bax activator, which blocks phosphorylation of S184 via binding to the C-terminal S184 site, did not affect this interaction. Additionally, an inhibitor for Hsp70-Hsp40 interaction blocked the Bax-Hsp70 interaction. Furthermore, p53 activators promoted the dissociation of Bax from Hsp70 by reactivating p53 which disrupted the Bax-Hsp70 interaction. We also found that death ligands and a Bcl-2 inhibitor enhanced the dissociation of Bax from Hsp70 by activating activator BH3-only proteins. Results from this effort suggest that FRET systems consisting of the ANAP-incorporated protein and the YFP fusion protein will be valuable tools to gain an understanding of other types of protein-protein interactions.

Quorum sensing (QS) inhibitor-based therapy is an attractive strategy to inhibit bacterial biofilm formation without excessive induction of antibiotic resistance. Thus, we designed Ca 2+ -binding poly(lactide- co-glycolide) (PLGA) microparticles that can maintain a sufficient concentration of QS inhibitors around hydroxyapatite (HA) surfaces in order to prevent biofilm formation on HA-based dental or bone tissues or implants and, therefore, subsequent pathogenesis. Poly(butyl methacrylate- co-methacryloyloxyethyl phosphate) (PBMP) contains both Ca 2+ -binding phosphomonoester groups and PLGA-interacting butyl groups. The PBMP-coated PLGA (PLGA/PBMP) microparticles exhibited superior adhesion to HA surfaces without altering the sustained release properties of uncoated PLGA microparticles. PLGA/PBMP microparticle-encapsulating furanone C-30, a representative QS inhibitor, effectively inhibited the growth of Streptococcus mutans and its ability to form biofilms on HA surface for prolonged periods of up to 100 h, which was much longer than either furanone C-30 in its free form or when encapsulated in noncoated PLGA microparticles.

To address drug resistance to HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), a series of novel diarylpyrimidine (DAPY) derivatives targeting "tolerant region I" and "tolerant region II" of the NNRTIs binding pocket (NNIBP) were designed utilizing a structure-guided scaffold-hopping strategy. The dihydrofuro[3,4- d]pyrimidine derivatives 13c2 and 13c4 proved to be exceptionally potent against a wide range of HIV-1 strains carrying single NNRTI-resistant mutations (EC 50 = 0.9-8.4 nM), which were remarkably superior to that of etravirine (ETV). Meanwhile, both compounds exhibited comparable activities with ETV toward the virus with double mutations F227L+V106A and K103N+Y181C. Furthermore, the most active compound 13c2 showed favorable pharmacokinetic properties with an oral bioavailability of 30.96% and a half-life of 11.1 h, which suggested that 13c2 is worth further investigation as a novel NNRTI to circumvent drug resistance.

Xanthatin (XT), a naturally occurring sesquiterpene lactone presented in cocklebur ( Xanthium strumarium L.), is under development as a potential anticancer agent. Despite the promising anticancer effect of XT, the molecular mechanism underlying its cellular action has not been well elucidated. The mammalian thioredoxin reductase (TrxR) enzymes, the essential seleno-flavoproteins containing a penultimate selenocysteine (Sec) residue at the C-terminus, represent a promising target for cancer chemotherapeutic agents. In this study, XT inhibits both the purified TrxR and the enzyme in cells. The possible binding mode of XT with the TrxR protein is predicted by the covalent docking method. Mechanism studies reveal that XT targets the Sec residue of TrxR and inhibits the enzyme activity irreversibly. Simultaneously, the inhibition of TrxR by XT promotes the oxidative stress-mediated apoptosis of HeLa cells. Importantly, the knockdown of the enzyme sensitizes the cells to XT treatment. Targeting TrxR thus discloses a novel molecular mechanism in accounting for the cellular action of XT and provides insights into the development of XT as an anticancer agent.

Inhibitors of phosphodiesterases (PDEs) have been widely studied as therapeutics for the treatment of human diseases, but improvement of inhibitor selectivity is still desirable for the enhancement of inhibitor potency. Here, we report identification of a water-containing subpocket as a PDE4-specific pocket for inhibitor binding. We designed against the pocket and synthesized two enantiomers of PDE4 inhibitor Zl-n-91. The ( S)-Zl-n-91 enantiomer showed IC 50 values of 12 and 20 nM for the catalytic domains of PDE4D2 and PDE4B2B, respectively, selectivity several thousand-fold greater than those of other PDE families, and potent neuroprotection activities. Crystal structures of the PDE4D2 catalytic domain in complex with each Zl-n-91 enantiomer revealed that ( S)-Zl-n-91 but not ( R)-Zl-n-91 formed a hydrogen bond with the bound water in the pocket, thus explaining its higher affinity. The structural superposition between the PDE families revealed that this water-containing subpocket is unique to PDE4 and thus valuable for the design of PDE4 selective inhibitors.

Inhibition of phosphodiesterase 4 (PDE4) suppressed the inflammatory responses in the brain. However, the underlying mechanisms are poorly understood. Roflupram (ROF) is a novel PDE4 inhibitor. In the present study, we found that ROF enhanced the level of microtubule-associated protein 1 light chain 3 II (LC3-II) and decreased p62 in microglial BV-2 cells. Enhanced fluorescent signals were observed in BV-2 cells treated with ROF by Lysotracker red and acridine orange staining. In addition, immunofluorescence indicated a significant increase in punctate LC3. Moreover, β amyloid 25-35 (Aβ 25-35 ) or lipopolysaccharide (LPS) with ATP was used to activate inflammasome. We found that both LPS plus ATP and Aβ 25-35 enhanced the conversion of pro-caspase-1 to cleaved-caspase-1 and increased the production of mature IL-1β in BV-2 cells. Interestingly, these effects were blocked by the treatment of ROF. Consistently, knocking down the expression of PDE4B in primary microglial cells led to enhanced level of LC-3 II and decreased activation of inflammasome. What's more, Hoechst staining showed that ROF decreased the apoptosis of neuronal N2a cells in conditioned media from microglia. Our data also showed that ROF dose-dependently enhanced autophagy, reduced the activation of inflammasome and suppressed the production of IL-1β in mice injected with LPS. These effects were reversed by inhibition of microglial autophagy. These results put together demonstrate that ROF inhibits inflammasome activities and reduces the release of IL-1β by inducing autophagy. Therefore, ROF could be used as a potential therapeutic compound for the intervention of inflammation-associated diseases in the brain.

Citrifurans A-D (1-4), metabolized by an Aspergillus sp., are unusual dimers of azaphilone and furanone derivatives. Michael addition was thought to be the pivotal procedure in their biosynthesis, and different addition sites generated two new different carbon skeletons. Their structures were elucidated on the basis of spectroscopic methods, single-crystal X-ray diffraction, chemical conversion, and electronic circular dichroism analyses. Compounds 1-3 showed moderate inhibitory activities against LPS-induced NO production in RAW 264.7 macrophages with IC 50 values of 18.3, 22.6, and 25.3 μM, respectively.

Design, synthesis, and evaluation of a new class of exceptionally potent HIV-1 protease inhibitors are reported. Inhibitor 5 displayed superior antiviral activity and drug-resistance profiles. In fact, this inhibitor showed several orders of magnitude improved antiviral activity over the FDA approved drug darunavir. This inhibitor incorporates an unprecedented 6-5-5 ring-fused crown-like tetrahydropyranofuran as the P2 ligand and an aminobenzothiazole as the P2' ligand with the (R)-hydroxyethylsulfonamide isostere. The crown-like P2 ligand for this inhibitor has been synthesized efficiently in an optically active form using a chiral Diels-Alder catalyst providing a key intermediate in high enantiomeric purity. Two high resolution X-ray structures of inhibitor-bound HIV-1 protease revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insight into the binding properties of these new inhibitors.

Arctiin is the most abundant bioactive compound contained in the Arctium lappa plant. In our previous study, we isolated one single bacterium capable of bioconverting arctigenin, an aglycone of arctiin, to 3'-desmethylarctigenin (3'-DMAG) solely. However, to date, a specific bacterium capable of producing other arctiin metabolites has not been reported. In this study, we isolated one single bacterium, which we named Eggerthella sp. AUH-JLD49s, capable of bioconverting 3'-DMAG under anaerobic conditions. The metabolite of 3'-DMAG by strain AUH-JLD49s was identified as 3'-desmethyl-4'-dehydroxyarctigenin (DMDH-AG) based on electrospray ionization mass spectrometry (ESI-MS) and 1 H and 13 C nuclear magnetic resonance spectroscopy. The bioconversion kinetics and bioconversion capacity of strain AUH-JLD49s were investigated. In addition, the metabolite DMDH-AG showed an inhibitory effect on cell growth of human colon cancer cell line HCT116 and human breast cancer cell line MDA-MB-231.

The regulation of brain monoamine levels is paramount for cognitive functions, and the monoamine oxidase (MAO A and B) enzymes play a central role in these processes. The aim of this study was to evaluate whether the procognitive properties exerted by propargylamine N-(furan-2-ylmethyl)-N-methylprop-2-yn-1-amine (F2MPA) are related to changes in monoamine content via MAO inhibition. In vivo microdialysis and ex vivo amine metabolite measurement demonstrated region-specific alterations in monoamine metabolism that differ from both of the classic MAO A and MAO B inhibitors, clorgyline and l-deprenyl, respectively. Although all the inhibitors (1 and 4 mg/kg) increased cortical serotonin tissue content, only F2MPA increased the levels of cortical noradrenaline. In the striatum, clorgyline (1 mg/kg), but not F2MPA (1 mg/kg), reduced extracellular levels of dopamine metabolites at rest or stimulated by the intrastriatal application of the MAO substrate 3-methoxytyramine. In vitro, F2MPA exhibited a low affinity toward MAO B and MAO A. Nonetheless, it modified the B form of MAO, forming a flavin adduct structurally similar to that with deprenyl. F2MPA was rapidly metabolized in the presence of rat but not human microsomes, producing a hydroxylated derivative. In conclusion, the effect of F2MPA on cognition may arise from monoaminergic changes in the cortex, but the role of MAO in this process is likely to be negligible, consistent with the poor affinity of F2MPA for MAO.

Arctigenin is a lignan abundant in Asteraceae plants and has anti-inflammatory, antiobesity, and anticancer activities. Obesity is one of the leading causes of several types of cancers including breast cancer. The current study was performed to investigate if arctigenin suppresses differentiation of preadipocytes and proliferation of breast cancer cells and to explore potential molecular mechanisms. Treatment of arctigenin reduced lipid accumulation in differentiated 3T3-L1 adipocytes in a dose- and time-dependent manner without toxicity. Arctigenin suppressed the expression of peroxisome proliferator-activated receptor-gamma (PPARγ), CCAAT/enhancer-binding protein-alpha (C/EBPα), perilipin, and fatty acid binding protein 4 (FABP4) in a dose-dependent manner in differentiated 3T3-L1 cells. Both total and unphosphorylated (active) β-catenin were increased in whole cell lysates and the nuclear fraction of differentiated 3T3-L1 cells treated with 25 μM arctigenin. On the other hand, arctigenin decreased proliferation of two human breast cancer cells (MCF-7 and MDA-MB-231). Arctigenin induced apoptosis and decreased expression of total and unphosphorylated (active) β-catenin and cyclin D1 in MCF-7, but not in MDA-MB-231. These data indicate that arctigenin suppressed adipogenesis in preadipocytes and activated apoptosis in estrogen receptor (ER) positive breast cancer cells through modulating expression of β-catenin.

CMPF (2-(2-carboxyethyl)-4-methyl-5-propylfuran-3-carboxylic acid) is a metabolite that circulates at high concentrations in type 2 and gestational diabetes patients. Further, human clinical studies suggest it might have a causal role in these diseases. CMPF inhibits insulin secretion in mouse and human islets in vitro and in vivo in rodents. However, the metabolic fate of CMPF and the relationship of structure to effects on insulin secretion have not been significantly studied. The syntheses of CMPF and analogues are described. These include isotopically labeled molecules. Study of these materials in vivo has led to the first observation of a metabolite of CMPF. In addition, a wide range of CMPF analogues have been prepared and characterized in insulin secretion assays using both mouse and human islets. Several molecules that influence insulin secretion in vitro were identified. The molecules described should serve as interesting probes to further study the biology of CMPF.

The synthesis, the enantiomeric separation, and the characterization of new simple spiroketal derivatives have been performed. The synthesized compounds have shown a very high anticancer activity. Cell proliferation assay showed that they induce a remarkable inhibition of cell proliferation in all cell lines treated, depending on culture time and concentration. The compounds have also shown a potent nanomolar human telomerase inhibition activity and apoptosis induction. CD melting experiments demonstrate that spiroketal does not affect the G-quadruplex (G4) thermal stability. Docking studies showed that telomerase inhibition could be determined by a spiroketal interaction with the telomerase enzyme.

Screening of a small compound library at the three excitatory amino acid transporter subtypes 1-3 (EAAT1-3) resulted in the identification of compound (Z)-4-chloro-3-(5-((3-(2-ethoxy-2-oxoethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid (1a) that exhibited a distinct preference as an inhibitor at EAAT1 (IC 50 20 μM) compared to EAAT2 and EAAT3 (IC 50 > 300 μM). This prompted us to subject 1a to an elaborate structure-activity relationship study through the purchase and synthesis and subsequent pharmacological characterization of a total of 36 analogues. Although this effort did not result in analogues with substantially improved inhibitory potencies at EAAT1 compared to that displayed by the hit, it provided a detailed insight into structural requirements for EAAT1 activity of this scaffold. The discovery of this new class of EAAT1-selective inhibitors not only supplements the currently available pharmacological tools in the EAAT field but also substantiates the notion that EAAT ligands not derived from α-amino acids hold considerable potential in terms of subtype-selective modulation of the transporters.

In this study, we report a new dipeptide functionalization strategy for developing new dendritic bolaamphiphile vectors for efficient siRNA transfection. A focused library of dipeptides was constructed using four amino acids: l-arginine, l-histidine, l-lysine, and l-tryptophan. The dipeptides were coupled to two dendritic bolaamphiphile scaffolds that we developed previously, allowing us to quickly access a focused library of discrete vectors with multivalent dendritic dipeptide functionalities. The resulting discrete bolaamphiphiles were screened for siRNA delivery in vitro in HEK-293 and HeLa cells. Bolaamphiphiles functionalized with dipeptides containing Lys or Arg and either His or Trp were the most effective for in vitro siRNA delivery. Necessary cationic charge to ensure efficient siRNA binding are provided by Arg and Lys residues, whereas endosomal escape is provided through pH responsive buffering of His or membrane interactions of Trp. The most effective vectors (F10 HR/RH) exhibited greater than 75% gene silencing in multiple cell lines and exhibited serum stability.

This is the first report on the ability of soy sauce to effectively reduce the serum uric acid levels and xanthine oxidase (XOD) activities of hyperuricemic rats. Soy sauce was partitioned sequentially into ethyl acetate and water fractions. The ethyl acetate fraction with strong XOD inhibition effect was purified further. On the basis of xanthine oxidase inhibitory (XOI) activity-guided purification, nine compounds including 3,4-dihydroxy ethyl cinnamate, diisobutyl terephthalate, harman, daidzein, flazin, catechol, thymine, genistein, and uracil were obtained. It was the first time that 3,4-dihydroxy ethyl cinnamate and diisobutyl terephthalate had been identified from soy sauce. Flazin with hydroxymethyl furan ketone group at C-1 and carboxyl at C-3 exhibited the strongest XOI activity (IC50 = 0.51 ± 0.05 mM). According to fluorescence quenching and molecular docking experiments, flazin could enter into the catalytic center of XOD to interact with Lys1045, Gln1194, and Arg912 mainly by hydrophobic forces and hydrogen bonds. Flazin, catechol, and genistein not only were potent XOD inhibitors but also held certain antioxidant activities. According to ADME (absorption, distribution, metabolism, and excretion) simulation in silico, flazin had good oral bioavailability in vivo.

This study was performed to isolate and identify a compound with antiproliferative activity against human stomach cancer cell lines, from fructose-tryptophan Maillard reaction products (MRPs). The MRPs, prepared from a fructose-tryptophan solution heated at 130 °C for 2 h, were fractionated into five solvent fractions: n-hexane, chloroform, ethyl acetate, butanol, and water. The highest antiproliferative activity was found in the chloroform fraction (85.93% at 200 μg/mL), and the active compound from this chloroform fraction was purified by silica gel column chromatography, TLC, and preparative HPLC. The antiproliferative activity (IC50) of the active compound was 42.24 μg/mL, and the active compound was identified as perlolyrine (C16H10N2O2) by (1)H/(13)C NMR, DEPT, HMBC, and LC-ESI-MS. Therefore, this research may be useful in developing perlolyrine as a functional therapeutic agent.

5-Arylbenzothiadiazine type compounds acting as positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-PAMs) have received particular attention in the past decade for their nootropic activity and lack of the excitotoxic side effects of direct agonists. Recently, our research group has published the synthesis and biological activity of 7-chloro-5-(3-furanyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide (1), one of the most active benzothiadiazine-derived AMPA-PAMs in vitro to date. However, 1 exists as two stereolabile enantiomers, which rapidly racemize in physiological conditions, and only one isomer is responsible for the pharmacological activity. In the present work, experiments carried out with rat liver microsomes show that 1 is converted by hepatic cytochrome P450 to the corresponding unsaturated derivative 2 and to the corresponding pharmacologically inactive benzenesulfonamide 3. Surprisingly, patch-clamp experiments reveal that 2 displays an activity comparable to that of the parent compound. Molecular modeling studies were performed to rationalize these results. Furthermore, mice cerebral microdialysis studies suggest that 2 is able to cross the blood-brain barrier and increases acetylcholine and serotonin levels in the hippocampus. The experimental data disclose that the achiral hepatic metabolite 2 possesses the same pharmacological activity of its parent compound 1 but with an enhanced chemical and stereochemical stability, as well as an improved pharmacokinetic profile compared with 1.

Oxidative damage is one of the most frequent types of DNA damage resulting from biologically generated oxygen or nitrogen reactive species. Hydroxyl radicals, one electron oxidants, and various chemical oxidants, such as permanganate and ozone, react with pyrimidine bases in DNA, cytosine and thymine, to produce 5-hydroxyhydantoin derivatives. 5-Hydroxyhydantoin modifications are interesting because they undergo ring-chain tautomerism into a pair of diastereomers via an open chain carbonyl intermediate. Here, we show that purified diastereomers of N1-(2-deoxy-β-D-erythro-pentofuranosyl)-5-hydroxy-5-methylhydantoin not only undergo isomerization into a mixture of 5R and 5S diastereomers of the hydantoin ring but also into three additional pairs of diastereomers, in which the sugar moiety transforms into α-furanose, β-pyranose, and α-pyranose anomers. The novel 5-hydroxy-5-methylhydantoin derivatives were characterized by extensive NMR analyses. Further studies indicate that isomerization is greatly suppressed at pH 6 compared to that at higher pH. A novel mechanism of isomerization is proposed to account for the formation of nucleoside anomers at neutral pH, which involves ring-chain tautomerism of both the hydantoin and sugar moieties. Last, the isomerization of β-furanose into the corresponding α-furanose is shown to take place in purified DNA, albeit to a slower extent than that in solution. The ability of 5-hydroxyhydantoin nucleosides to undergo isomerization may complicate the biological processing of this damage in cellular DNA.